This invention relates to novel substituted phenyl acetamides useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Bioloaical Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention provides compounds known as phenyl acetamides of the formula I 
wherein:
R1 is xe2x80x94H or xe2x80x94O(CH2)nZ;
R2 is xe2x80x94H or xe2x80x94OH;
R3 and R4 are each independently xe2x80x94H, halo or xe2x80x94(C1-C4)alkyl;
One of R5 and R6 is xe2x80x94YR7 and the other is xe2x80x94H, where Y is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94 and R7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, phenyl or phenyl substituted with one or two halo groups;
Z is xe2x80x94CO2R, xe2x80x94PO3R2 or xe2x80x94SO3R where R is xe2x80x94H or xe2x80x94(C1-C4)alkyl; and
n is 1-8;
or a pharmaceutically acceptable salt, racemate or optical isomer thereof;
provided that when R6 is YR7, R1 is hydrogen; and
when R1, R2, R3, R4 and R6 are hydrogen and R5 is YR7 
where Y is xe2x80x94Oxe2x80x94, R7 cannot be phenyl; and
when R1, R2, R3, R4 and R6 are hydrogen and R5 is YR7 where Y is CH2, R7 cannot be phenyl substituted with one methoxy or two chloro groups.
This invention is also a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention is also a method of inhibiting sPLA2 comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II. 
wherein:
R1 is xe2x80x94H or xe2x80x94O(CH2)nZ;
R2 is xe2x80x94H or xe2x80x94OH;
R3 and R4 are each independently xe2x80x94H, halo or xe2x80x94(C1-C4)alkyl;
one of R5 and R6 is xe2x80x94YR7 and the other is xe2x80x94H, where Y is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94 and R7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, phenyl or phenyl substituted with one or two halo groups;
Z is xe2x80x94CO2R, xe2x80x94PO3R2 or xe2x80x94SO3R where R is xe2x80x94H or xe2x80x94(C1-C4)alkyl; and
n is 1 to 8;
or a pharmaceutically acceptable salt, racemate or optical isomer thereof.
According to a further aspect of the present invention, there is provided a method of inhibiting SPLA2 in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula (II).
According to a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA2 in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula (II).
This invention also provides a method of alleviating the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula II in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic and cascade and its deleterious products.
Other objects, features and advantages of the resent invention will become apparent from the subsequent description and the appended claims.
Definitions:
As used herein, the term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl and the like.
The term xe2x80x9chaloxe2x80x9d means chloro, fluoro, bromo or iodo.
The term xe2x80x9c(C1-C4) alkoxyxe2x80x9d, as used herein, denotes a straight or branched alkyl chain having one to four carbon atoms attached to the remainder of the molecule by an oxygen atom. Typical C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.
The salts of the above phenyl acetamides are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cpharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)).
Examples of pharmaceutically acceptable organic bases which may be used to prepare pharmaceutically acceptable salts include ammonia, amines such as triethanolamine, triethylamine, ethylamine, and the like. Examples of pharmaceutically acceptable alkali metal bases include compounds of the general formula MOR12, where M represents an alkali metal atom, e.g. sodium, potassium, or lithium, and R12 represents hydrogen or C1-C6 alkyl.
The term xe2x80x9cacid protecting groupxe2x80x9d is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 5 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety.
Examples of acid protecting groups includes esters and substituted esters such as methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, p-bromobenzyl and trimethylsilyl. A preferred acid-protecting group is methyl.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. For example, compounds where R2 is xe2x80x94OH have a chiral center and form a racemate. The Rxe2x80x94 and Sxe2x80x94 isomers and mixtures thereof, including racemic mixtures are contemplated by this invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
Preferred groups include the following:
(a) R1 is xe2x80x94H;
(b) R1 is xe2x80x94O(CH2)nZ
(c) R2 is xe2x80x94H;
(d) R2 is xe2x80x94OH;
(e) R3 and R4 are each xe2x80x94H;
(f) R6 is xe2x80x94YR7 and R7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, phenyl or phenyl substituted with halo;
(g) R5 is xe2x80x94YR7 where Y is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94 and R7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, phenyl or phenyl substituted with halo;
(h) R7 is phenyl substituted at the meta positions with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, xe2x80x94CF3, phenyl or phenyl substituted at the para position with halo;
(i) R7 is phenyl substituted at the ortho positions with one or two substituents selected from the group consisting of halo, xe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy, xe2x80x94CF3, phenyl or phenyl substituted at the para position with halo;
(j) R7 is phenyl or phenyl substituted with halo;
(k) Z is xe2x80x94CO2H, xe2x80x94PO3H2 or xe2x80x94SO3H; and
(l) n is 4-5.
Further typical examples of compounds of formula I which are useful in the present invention include:
4-(2,6-difluorophenoxy)-5-ethylphenylacetamide;
4-(3-ethoxyphenoxy)-6-chlorophenylacetamide;
4-(5-isopropylphenoxy)-5,6-dichlorophenylacetamide;
3-(4-methylphenoxy)-phenylacetamide;
4-(3,5-diphenylphenoxy)-5-bromophenylacetamide;
4-(4-(3,5-difluorophenyl)phenoxy)-6-methylphenylacetamide;
3-((3-propoxy-5-t-butyl)phenoxy)-phenylacetamide;
3-(2,6-di(4-fluorophenyl)phenoxy)-5, 6-dimethylphenylacetamide;
4-(3,5-di-t-butylphenoxy)-5-butylphenylacetamide;
3-(4-(2-bromophenyl)phenoxy)-6-ethylphenylacetamide;
4-(5-chlorophenoxy)-5-propylphenylacetamide;
3-(2-chloro-6-ethoxyphenoxy)-5-chlorophenylacetamide;
4-(2,6-dimethyl)benzyl-5-butylphenylacetamide;
3-(3-propoxy)benzyl-6-ethylphenylacetamide;
3-(5-phenyl)benzyl-5,6(di-t-butyl)phenylacetamide;
3-(4-ethyl)benzylphenylacetamide;
4-(3,5-diphenyl)benzyl-5-chlorophenylacetamide;
3-(4-(3,5-di(4-fluorophenyl)))benzyl-6-butylphenylacetamide;
4-(3-methoxy-5-isopropyl)benzylphenylacetamide;
3-(2,6-diphenyl)benzyl-5,6-dibutylphenylacetamide;
3-(3,5-dimethyl)benzyl-5-fluorophenylacetamide;
4-(4-ethyl)benzyl-5-butylphenylacetamide;
3-(5-bromo)benzyl-5-ethylphenylacetamide;
4-(2,6-diphenyl)benzyl-5,6-dimethylphenylacetamide;
4-(2-methyl-6-methoxy)benzyl-6-fluorophenylacetamid;
2-(3-carboxyprop-1-yloxy)-4-(4-phenylphenoxy) phenyl-2-hydroxyacetamide;
2-(2-carboxyethoxy)-4-(2,6-di(3-chlorophenyl)phenoxy)phenyl-2-hydroxyacetamide;
2-[2-(carboxymethoxy)-4-(3,5-dimethoxyphenoxy)-5-methyl]phenyl-2-hydroxyacetamide;
2-[2-(5-carboxypent-1-yloxy)-4-(phenoxy)-6-hlorolphenyl-2-hydroxyacetamide;
2-[2-(8-carboxyoct-1-yloxy)-4-(2, 6-dimethylphenoxy)-5-fluoro]phenyl-2-hydroxyacetamide;
2-[2-(2-phosophonyl)ethoxy-4-(4-propoxyphenoxy)-6-isopropyl]phenyl-2-hydroxyacetamide;
2-((3-dimethoxyphosphonoly)prop-1-yloxy)-4-(3,5 diethoxy)benzyl-6-ethylphenylacetamide;
2-[2-(diethoxyphosphonoyl)methoxy)-4-phenoxy]phenyl-2-hydroxyacetamide;
2-[2-((8-methoxycarbonyl)oct-1-yloxy)-4-(3-phenylbenzyl)-6-butyl]phenyl-2-hydroxyacetamide;
2-[2-(methoxysulfonyl)methoxy-4-(4-(3,5-di(4-fluorophenyl)phenoxy)-5-ethyl)phenyl-2-hydroxyacetamide;
2-[2-(4-sulfonyl)but-1-yloxy)-4-(4-methoxyphenoxy)-6-fluoro]phenyl-2-hydroxyacetamide;
2-[2-(3-carbomethoxy)prop-1-yloxy)-4-(2, 6-difluorophenoxy)-5-ethyl]phenyl-2-hydroxyacetamide;
2-[2-(2-ethoxycarbonyl)ethoxy-4-benzyl]phenyl-2-hydroxyacetamide;
2-[2-((3-propoxycarbonyl)prop-1-yloxy)-4-(4-(4-chlorophenyl)benzyl)]phenyl-2-hydroxyacetamide;
2-[2-(6-diethoxyphosphonyl)hex-1-yloxy)-4-(3-ethyl-5-methoxyphenoxy)]phenyl-2-hydroxyacetamide;
2-[2-(7-methoxysulfonyl)hept-1-yloxy)-4-((2-fluoro-6-phenyl)benzyl)]phenyl-2-hydroxyacetamide;
2-[2-(3-carboxyprop-1-yloxy)-4-(3-phenylphenoxy)]phenyl-2-hydroxyacetamide:
2-(2-phosphonyl)ethoxy-4-(3-propoxyphenoxy)-5-propylphenylacetamide;
2-((4-diethoxyphosphonyl)but-1-yloxy)-4-(5-t-butylphenoxy)-6-ethylphenylacetamide;
2-(6-phosphonyl)hex-1-yl)-4-(2, 6-dimethylphenoxy)phenylacetamide;
2-((3-diethoxyphosphonyl)prop-1-yloxy)-4-(3-fluoro-5-ethoxybenzyl)-6-methylphenylacetamide;
2-(methoxysulfonyl)methoxy-4-(4-(4-fluorophenyl)benzyl)-6-ethylphenylacetamide;
2-((4-ethoxycarbonyl)but-1-yloxy)-4-benzylphenylacetamide;
2-(2-ethoxycarbonyl)ethoxy-4-(3, 5-diphenylphenoxy)phenylacetamide;
2-(4-(propoxycarbonyl)but-1-yloxy)-4-(4-butoxyphenoxy)phenylacetamide;
2-(8-methoxycarbonyl)oct-1-yloxy)-4-(3-bromo-5-methylbenzyl)-5-propylphenylacetamide;
2-(4-carboxybutoxy)-4-(3-phenylphenoxy)phenylacetamide;
Compounds of formula I where R1 and R2 are H, R5 or R6 are YR7 where R7 is phenyl or substituted phenyl and Y is oxygen can be prepared as illustrated in Scheme I(a), below. 
X is halo;
R8 and R9 are each independently xe2x80x94H, halo, xe2x80x94(C1-C4)alkyl, (Cl-C4)alkoxy,
phenyl or phenyl substituted with one or two halo groups; and PG is a carboxyl protecting group
An appropriately substituted carboxy-protected halophenyl compound (1), where the halogen is preferably bromine, is coupled with an appropriately substituted phenol (2) under modified Ullmann conditions, by refluxing with potassium carbonate and cupric oxide in an aprotic polar solvent, such as pyridine, under an inert gas such as argon. The reaction is substantially complete in 1-24 hours.
Intermediate (3) is deprotected by treatment with a base such as aqueous potassium hydroxide using a solvent, such as diethylene glycol. The reaction, preferably conducted at about 100xc2x0-150xc2x0 C., is substantially complete in 1-24 hours.
Conversion to the amide (5) can then be readily achieved by treatment first with oxalyl chloride in an alkyl halide solvent, such as methylene chloride, using dimethylformamide as a catalyst, at temperatures of from about 0xc2x0 C. to ambient temperature, followed by treatment with an excess of ammonia gas, again in an alkyl halide solvent.
Alternately, compounds of formula I can be prepared according to the procedure of Scheme I(b), below.
The substituted phenol (2) is coupled with an appropriately substituted benzyl halide (6) as described in Scheme I(a), step a, above, to prepare (7).
Halogenation of (7) is achieved using a halogenating agent, such as N-bromosuccinimide and a catalyst, such as 2,2xe2x80x2azobisisobutyronitrile, in an alkyl halide solvent, such as chloroform, to prepare (8).
Treatment of (8) with sodium cyanide in an aprotic polar solvent, such as dimethyl formamide produces the nitrile (9) which can then be readily converted to the amide (10) by treatment with an aqueous acid, such as hydrochloric acid. 
R8 and R9 are as shown Shceme I(a),
x is halo.
In another procedure, compounds of formula I where R1,R2,R3, and R4 are hydrogen, Y is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94 and R7 is phenyl can be prepared as portrayed in Scheme II on the following page. 
X is a halogen.
An appropriate diphenyl compound (11) is treated with paraformaldehyde and a halogenating agent, such as 40% hydrogen bromide in acetic acid. Two positional isomers result with the X substituent at either the meta or para position of the phenyl ring to which it is attached.
Displacement of the halogen to prepare the nitrile isomers (13) can be achieved by treatment of (12) with sodium cyanide in dimethylformamide as described in Scheme I(b), step (c), above. The isomers can then be readily separated by conventional chromatographic techniques and each isomer may be converted to its respective amide (14) by treatment with hydrogen peroxide and potassium carbonate in an aprotic polar solvent, such as dimethylsulfoxide.
Compounds where R1 is xe2x80x94O(CH2)nZ can be prepared as illustrated in Scheme III, below. 
R is xe2x80x94(C1-C4)alkyl and
p=1 or 2.
Intermediate (16) is prepared by refluxing an appropriately substituted diphenyl compound (15) with oxalyl chloride in an alkyl halide solvent, such as chloroform. Preferably the reaction is catalyzed with 4,4-N-dimethylaminopyridine.
Cyclization to the lactone (17) can be achieved under Friedel-Crafts conditions using a suitable metal halide, such as aluminum chloride, as the catalyst.
Conversion to the glyoxamide (18) can be achieved by aminolysis of the lactone ring using concentrated ammonium hydroxide.
Alkylation of the hydroxy group to prepare the desired alkyl-linked ester (19) occurs by treatment of (18) with an appropriate alkylating agent, such as (X) (CH2)nB where B is CO2PG, xe2x80x94PO3PG or xe2x80x94SO3PG, X is halo and PG is an acid protecting group, preferably methyl.
Partial reduction of the carbonyl in the glyoxamide (19) is achieved by treatment with a suitable reducing agent, such as sodium borohydride in methanol, preferably at temperatures of from 0xc2x0-20xc2x0 C., to prepare the intermediate (20). The desired acid or acid salt (21) can be accomplished by treatment with a suitable base, such as sodium hydroxide.
Further reduction of intermediate (20) can be achieved by treatment with triethylsilane in a strong acid, such as trifluroacetic acid, under an inert gas, such as argon, to prepare (22) followed, again, by conversion to the acid or salt (23) with a strong base.
It will be readily appreciated by the skilled artisan that the starting materials are either commercially available or can be readily prepared by known techniques from commercially available starting materials. For example, when X is oxygen, starting material (15) can be readily prepared by coupling an appropriately substituted phenol with an appropriately substituted phenylhalide to prepare the anisole, under Ullmann-type conditions, by refluxing in the presence of an excess of potassium carbonate and cupric oxide in an aprotic polar solvent such as pyridine. The reaction is preferably conducted under a argon blanket and is substantially complete in from 1 to 48 hours.
Compounds of formula I where Y is xe2x80x94CH2xe2x80x94 can be prepared as shown in Scheme IV. 
X is a halogen
Using an appropriately substituted phenyl halide, a Grignard reagent (25) is prepared. The phenyl Grignard (25) is then coupled with nitrile (24) and the resultant compound is hydrolyzed with a dilute acid, such as hydrochloric acid to form the intermediate (26).
Reduction of the carbonyl in (26) is accomplished by treatment with a suitable reducing agent, such as sodium borohydride to prepare (27). The reaction is preferably conducted in a solvent catalyst, such as trifluroacetic acid.
The desired acetamide (28) may then be accomplished according to the procedures outlined in Scheme I(a), step (c).
The intermediates and final products may be isolated and purified by conventional techniques, for example by concentration of the solvents, followed by washing of the residue with water, then purification by conventional techniques such as chromatography or recrystallization.
It will be readily appreciated by the skilled artisan that the starting materials are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available.